All references, including any patents or patent application, cited in this specification are hereby incorporated by reference to enable full understanding of the invention. Nevertheless, such references are not to be read as constituting an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents.
Somatotropin or growth hormone (GH) is a potent anabolic hormone produced by the pituitary gland in daily doses of 0.5 to 0.8 mg in children and young adults. Its production decreases rapidly with age.
Human growth hormone (hGH) has a number of metabolic effects, the most prominent of which is its anabolic effect. HGH increases the influx of amino acids into the cell and decreases the efflux. Cell proliferation is accentuated as is overall protein synthesis and new tissue growth. HGH also stimulates insulin-like growth factor-1 (IGF-1) production by the liver and the anabolism seen with hGH is due to the action of IGF-1. Additionally, hGH, due to IGF-1 activity, is known to accelerate nucleic acid translation and transcription, increase nitrogen retention, increase protein synthesis, decrease cortisol receptor activity, increase hydrolysis of fats to fatty acids, increase fat oxidation for fuel thereby decreasing fat stores, increase metabolic rate, cause initial fluid retention, produce insulin resistance often leading to hyperglycemia and increase insulin requirements.
The predominant form of hGH is a globular protein with a molecular weight of 22 kilodaltons, consisting of 191 amino acid residues in a single-chain, folded by 2 disulphide bonds with a small loop at the carboxyl terminus between residues 182 and 189. Crystallographic studies show that hGH contains four anti-parallel α-helices which are arranged in a left-twisted, tightly-packed helical bundle. The concept that there are discrete functional domains within the hGH molecule responsible for specific metabolic actions of the hormone is generally accepted. The amino-terminus has been identified as the functional domain responsible for IGF-1 secretion and therefore the insulin-like actions of hGH (Ng (1990) New Antidiabetic Drugs pp 197-205). The carboxyl-terminus has been identified as a lipolytic domain of hGH (Ng F M et al., (2000) J. Mol. Endocrin. 25, 287-298).
HGH serves as a critical hormone in the regulation of cell and organ growth and in physiological function upon various stages of aging. For example, over-production of hGH results in gigantism in children and acromegaly in adults, whereas under-production leads to dwarfism in children, and chronic renal insufficiency. In adults, hGH deficiency can affect metabolic processing of proteins, carbohydrates, lipids, minerals and connective tissue and can result in muscle, bone or skin atrophy. Other hGH deficiency disorders characterized by growth failure include Prader-Willi syndrome, intrauterine growth retardation and catabolic state for example during chemotherapy treatment and in the treatment of AIDS.
Many scientific studies confirm that growth hormone treatment in adults improves the body composition (increasing the muscle mass and decreasing fat), bone density, muscle strength, cardiovascular parameters (i.e. decrease of LDL cholesterol), and the quality of life. Advanced acquired immunodeficiency syndrome (AIDS) is often accompanied by muscle wasting (“AIDS wasting”) and hGH has been shown to ameliorate this condition. HGH has been given to promote healing of large burns by reducing the amount of protein breakdown during the early post-injury period. HGH has been used as an adjunct to caloric restriction for obesity as hGH promotes lipolysis and reduces proteolysis. Several studies have demonstrated improvements in exercise capacity and cardiac function among hGH-deficient patients receiving hGH replacement. Such patients show increased oxygen uptake and power output during cycle ergometry associated with increased skeletal muscle mass and improved cardiac function.
It is widely accepted that the anabolic effects of hGH are mediated via secretion of IGF-1. Elevated IGF-1 may lead to reduced insulin sensitivity, increased hyperglycemic episodes, fluid retention, diabetes, acromegaly and some cancers. Accordingly, clinical applications of hGH are currently restricted.
It is an aim of an embodiment of the present invention to provide treatments for conditions that can be treated by growth hormone, without elevation of IGF-1.